RFG1

SW Hazardous Environmental Exposure

MMA(III), Gene Expression, and Cellular Transformation

Relevance to Swehsc : 

Arsenic is a ubiquitous toxicant to the Southwestern population due to exposure via drinking water, dust, and ingestion.  Arsenic is a known human carcinogen causing cancer at various sites and has a multitude of toxic effects.  The mechanism(s) of action for arsenic to cause its carcinogenic/toxic effect from exposure at environmentally relevant levels is unclear and is a major thrust of this RFG and the entire SWEHSC.  Establishing “safe” levels of exposure to arsenic is imperative to properly protect the susceptible Southwestern population.

Cluster of Efforts: 

Investigators: 

  • Bernard Futscher, PhD
  • A. Jay Gandolfi, PhD
  • Walter Klimecki, DVM, PhD
  • Catharine Smith, PhD
Milestones: 
  • We discovered that exposing human cells to levels of arsenic often found in real world situations, such as in drinking water from wells, produces new pathologic epigenetic landscapes that participate in the malignant transformation of human cells.  Specifically, we found that arsenical-mediated malignant transformation produces long range epigenetic changes in the cancer cell genome that disrupt normal structure and function, and more importantly that these epigenetic changes are common to multiple types of arsenical-induced cancers.  Importantly, this type of long range epigenetic damage that we saw arise in laboratory models of arsenic-induced malignant cancer are also an epigenetic hallmark also seen in “real world” cancers derived from cancer patients, including cancers of the bladder, prostate, lung , and breast.  Overall, these results indicate that arsenicals epigenetically target common regions of the genome across multiple cancer types.  Furthermore these results strongly implicate the destruction of the cell’s epigenetic landscape as a critical carcinogenic mechanism of action of environmental arsenicals. 
  • Disruption in energy metabolism was observed by measuring changes in carbohydrate metabolism in the BEAS-2B lung cell line.  This work helped establish a novel hypothesis that decreased levels of carbohydrate metabolites such as acetate and succinate will result in changes in carbohydrate-dependent changes in protein post-translational modification.  A pilot project has been initiated between Drs. Klimecki and Smith (RFG3) to investigate mitochrondrial protein acetylation in response to arsenic exposure.

Arsenic and Metabolic Studies

Relevance to Swehsc : 

In vivo studies investigated the role of arsenite and high fat diet in the metabolic profile in an outbred strain of mice, Swiss Webster.  Of relevance to human arsenic exposures, groups of mice were treated with arsenic in utero and post-natally. 

Cluster of Efforts: 

Investigators:

  • Todd Camenisch, PhD
  • Yin Chen, PhD
Milestones: 
  • Male mice exposed to arsenic in utero and also post-natally were relatively hyperglycemic when evaluating glucose and 1,5-anhydroglucose.  In contrast, the lipid profile of these mice had elevated levels of acetoacetate and 3-hydroxybutyrate, indicative of dysregulated nutrient sensing often found in diabetic patients.  Overall, in utero arsenic exposure appeared to predispose mice to metabolic disorder.  A hypothesis that will be further pursued in future grant submissions.
  • The gut microbiome of mice exposed to arsenic in utero and post-natally was also evaluated in Swiss Webster mice by the Chen laboratory.  Arsenic significantly decreased Clostridium coccoides, a universal gut commensal bacterial strain.  Interestingly, the bacterial decrease was more prevalent in male than female mice.

Dibutyl Phthalate Studies (DBP)

Relevance to Swehsc : 

Human exposure to DBP occurs daily as evidenced by the detection of its metabolites in spot human urine samples from subjects in the National Health and Nutrition Examination Survey (NHANES).  According to exposure estimates the largest source of DBP exposure to the general population is food and has been estimated to range between 7-10 µg/kg/day.  Notably, patients taking medications coated with DBP and workers exposed occupationally have exposure estimates that exceed those in the general population.  Specifically, it is estimated that patients taking medications coated with DBP are exposed to 1-233 µg/kg/day and individuals are exposed occupationally to 0.1-76 µg/kg/day.  Interestingly, human studies have also pointed out that among all age groups, women of reproductive age tend to have higher urinary levels of phthalate metabolites than older women or than men.  DBP is a chemical of concern in the study of breast cancer because it has been shown to bind and activate the estrogen receptor alpha, an important factor that stimulates growth of a large proportion of breast cancers.

Cluster of Efforts: 

Investigators:

  • Zelieann Craig, PhD
  • Richard Vaillancourt, PhD
Milestones: 
  • Dr. Zelieann Craig completed her post-doctoral training at the University of Illinois and is a recipient of a K99/R00 award.  Her research focus is reproductive toxicology.  She is currently investigating the role of dibutly phthalate on mouse ovarian function.  In addition, she and Dr. Vaillancourt have a pending pilot project application to investigate the synergistic effects of dibutly phthalate and EGF in breast cancer cells and mouse mammary gland.

TCE Teratogenicity in the Embryonic Heart

Relevance to Swehsc : 

Clean drinking water is precious in the arid Southwest.  One of the most ubiquitous pollutants to drinking water in the Southwest is trichloroethylene (TCE).  The carcinogenic potential of TCE was recently upgraded and our previous studies were the first to link TCE to heart birth defects in a human population.

Cluster of Efforts: 

Investigator:

  • Raymond Runyon, PhD
Milestones: 
  • The expression of specific CYPs in the embryonic heart early in development may explain the specific sensitivity of the developing heart to environmental agents prior to liver development.  This work was submitted to NIEHS for funding.  A pilot project has been funded to address reviewer comments on the R01.

Research

The SWEHSC plays an important role in stimulating collaborative interactions among researchers. This is evidenced by a significant number of new, funded research projects, as well as a notable number of planned initiatives involving collaborations. The SWEHSC promotes and enhances collaborative research within and between the members through Research Focus Groups.

The themes of the three Research Focus Groups are seen below.

Metabolic Disorders

The metabolism of arsenic refers to the way in which the substance is absorbed and excreted.  The efficiency of an individual’s metabolism of arsenic could dictate their risk of contracting disease.

Personal exposure measurement device development

Relevance to Swehsc : 

Studies in environmentally-exposed populations frequently suffer from poorly estimated individual exposures. Estimates such as average duration-weighted exposure levels are blunt instruments that obscure the sizeable fraction of individual exposures that deviate from the average.

Cluster of Efforts: 

Investigators/Funding: Tao (RFG1), Gandolfi (RFG1) ES010606

Milestones: 
  • This project aims to design and build a wearable personal monitoring device that updates exposure levels to a database via a Bluetooth connection to the user's cell phone.
  • Prototype built that reliably measures benzene levels and transmits them through Bluetooth connection.
  • Minimal interference from humidity and perfumes.
  • Dr. Tao has established collaborations with SWEHSC colleagues in the College of Public Health (Drs. Burgess and Beamer, RFG 2), resulting in a recently submitted collaborative grant to NIOSH to utilize this system to assess exposures to volatile pollutants for emergency workers. ES010606

 

Human Genetics of arsenic biotransformation

Relevance to Swehsc : 

Individual variation in the efficiency of metabolic arsenic methylation is one of the most consistently reported predictors of disease risk in arsenic-exposed human populations. Defining the genetic and environmental determinants of arsenic methylation efficiency should establish easily measured biomarkers of increased susceptibility in an exposed population.

        

Cluster of Efforts: 

Investigators/Funding: Klimecki (RFG1), Gandolfi (RFG1), Billheimer (IHSFC-Biostats) NIEHS/ES004940 (Superfund Component Project)

Milestones: 
  • This epidemiology project is studying about 800 arsenic-exposed subjects from our geographical region, residing in Northern Sonora, Mexico. Demographic and questionnaire data, urine (for arsenic metabolite determination) and buccal swabs (for genetic variant testing) are being collected.
  • A detailed characterization of chromosome 10 surrounding AS3MT,the key arsenic metabolic gene, revealed an extraordinarily large region of linkage disequilibrium (LD) that spans nearly 400,000 bases at very high LD, potentially confounding genetic association studies of arsenic metabolism.
  • Replicating the first published genetic association of AS3MT with arsenic metabolism (our report), intronic variants in AS3MT were shown to be associated with more efficient arsenic methylation, however this is complicated by the occurrence of these variants within the extremely large cluster of linked polymorphisms that spans 5 genes.
  • Quantitative ascertainment of ancestry using a set of 90 ancestry informative marker SNPs suggests that arsenic methylation efficiency is positively correlated with the fraction of indigenous ancestry in mestizo populations. NIEHS/ES004940 (Superfund Component Project)

 

Modification of the epigenetic landscape by arsenic

Relevance to Swehsc : 

The absence of mechanistic explanations for the increased risk of cancers from arsenic exposure in humans confounds regulators and hinders progress in mitigation of risk in exposed populations. A growing body of data suggests that one key mechanism of arsenic may be the perturbation of epigenetic gene regulation.

Cluster of Efforts: 

Investigators/Funding: Futscher (RFG1), Gandolfi (RFG1), Klimecki (RFG1, IHSFC) NCI/CA015159

             

Milestones: 
  • This grant, awarded under a joint NIEHS/NCI RFA, studies the epigenetic status of both human cell lines exposed to arsenic, as well as exfoliated bladder cells from exposed human study participants exposed to arsenic at defined low and high levels of arsenic exposure. NCI/CA015159
  • Arsenic exposure to UROtsa cell lines alters the levels of siRNA species with defined involvement in epigenetic gene regulation
  • Genome-wide measurement of epigenetic marks on DNA from exfoliated bladder cells from arsenic-exposed people, analyzed by principal component analysis, result in segregation of the samples into clusters of low exposure and high exposure individuals, suggesting that the epigenetic landscape is modified by arsenic and that epigenetic signatures may be promising biomarkers of arsenic exposure and disease. NIEHS/ES004940, NCI/CA015159

 

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